S-t-BUTYL PROTECTED CYSTEINE DI-PEPTIDE ANALOGS AND RELATED COMPOUNDS

ABSTRACT

S-t-butyl protected cysteine di-peptide analogs and related compounds and methods of using these compounds for the treatment of diseases and/or conditions, including but not limited to diseases and/or conditions of Central Nervous System (CNS).

FIELD OF THE INVENTION

This invention relates to novel S-t-butyl protected cysteine di-peptideanalogs and related compounds and methods of using these compounds forthe treatment of diseases and/or conditions, including but not limitedto diseases and/or conditions of Central Nervous System (CNS).

BACKGROUND OF THE INVENTION

Diseases and/or conditions of the Central Nervous System (CNS) affect alarge number of people. One of the CNS disorders, schizophrenia, is adebilitating disorder afflicting 1% of the world's population. Thedevelopment of effective medications to treat schizophrenia relies onadvances in characterizing the underlying pathophysiology.

Conventional approaches to treating schizophrenia and other CNSdisorders have significant disadvantages, including suboptimal efficacyand/or side effects associated with their use. For example, existingfirst and second generation antipsychotic agents have a number ofshortcomings and significant side effects, such as extrapyramidal sideeffects, endocrine effects, obesity, elevated triglycerides, bloodpressure and glucose levels, type II diabetes, cardiovascular disease,renal toxicity and agranulocytosis. Thus, it is desirable to developnovel agents that can improve treatment outcomes and safety.

Accordingly, there is a significant need for new therapeutical agents totreat disorders of the CNS.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to compounds of formulaI:

whereR¹ is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂,CH₂-phenyl, and phenyl;R⁴ is selected from the group consisting of H, C(O)R₂, and

R² is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂,CH₂-phenyl, and phenyl; andR³ is selected from the group consisting of H, CH₃, CH₂-phenyl,CH(CH₃)₂, CH₂OH,

In another aspect, the present invention is directed to compounds offormula II:

whereR¹ is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂,CH₂-phenyl, and phenyl;R⁴ is selected from the group consisting of H and

R² is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂,CH₂-phenyl, and phenyl; andR³ is selected from the group consisting of H, CH₃, CH₂-phenyl,CH(CH₃)₂, CH₂OH,

The invention also encompasses pharmaceutically acceptable salts, estersand prodrugs of the provided compounds.

In another aspect, the invention is directed to a method of treating adisease or condition in a subject comprising administering to thesubject a therapeutically effective amount of a compound of any ofFormulas I or II or a pharmaceutically acceptable salt thereof. Thepreferred route of administering to the subject is via oral delivery.Preferably, diseases or conditions treatable with the compounds of thepresent invention are related to central nervous system (CNS).

In another aspect, the present invention provides methods of treating adisease or condition of the Central Nervous System (CNS), including butnot limited to schizophrenia, drug craving, drug addiction, bipolardisorder, anxiety, depression, Parkinson's disease, Alzheimer's disease,cognitive dysfunction, multiple sclerosis, Amyotrophic lateral sclerosis(ALS), ischemic stroke, HIV dementia, and Huntington's diseasecomprising administering to a subject in need thereof a therapeuticallyeffective amount of any of the inventive compounds.

In a preferred embodiment, the disease is schizophrenia.

In some aspects, the methods and compositions of the invention may beused in combination with conventional first and second generationanti-psychotic agents.

Thus, in one embodiment, the invention is directed to a combinationaluse of: 1) a compound of any of Formulas I-II and 2) pre-existing firstgeneration anti-psychotic agents (including but not limited tochlorpromazine, thioridazine, mesoridazine, loxapine, molindone,perphenazine, thiothixene, trifluoperazine, haloperidol, fluphenazine,droperidol, zuclopenthixol and prochlorperazineperphenazine) and/orsecond generation anti-psychotic agents (including but not limited toamisulpride, aripiprazole, asenapine, blonanserin, clotiapine,clozapine, iloperidone, lurasidone, mosapramine, olanzapine,paliperidone, perospirone, quetiapine, remoxipride, risperidone,sertindole, sulpiride, ziprasidone, zotepine, bifeprunox (DU-127,090),pimavanserin (ACP-103), and vabicaserin (SCA-136) for the treatment of adisease or condition of CNS, including but not limited to schizophrenia,drug craving, drug addiction, bipolar disorder, anxiety, depression,Parkinson's disease, Alzheimer's disease, cognitive dysfunction,multiple sclerosis, ALS, ischemic stroke, HIV dementia, and Huntington'sdisease.

The invention further encompasses pharmaceutical compositions containinga compound of any of Formulas I or II or a pharmaceutically acceptablesalt thereof in combination with a pharmaceutically-acceptable carrier.

Methods of formulating/manufacturing such pharmaceutical compositions(alternatively termed “medicaments”) for the treatment of a disease orcondition in a subject are also within the invention's scope.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described.

The term “t-butyl” refers to tert-butyl alkyl group.

The term “DBU” refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

The term “CDI” refers to 1,1′-carbonyldiimidazole.

The term “HOBt” refers to hydroxybenzotriazole.

The term “EDCI” refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,which is a coupling agent.

The term “prodrugs” refers to compounds, including but not limited tomonomers and dimers of the compounds of the invention, which becomeunder physiological conditions compounds of the invention or the activemoieties of the compounds of the invention.

The term “active moieties” refers to compounds which arepharmaceutically active in vivo, whether or not such compounds arecompounds of the invention.

The term “ester” refers to compounds having a generic structure ofRCO₂R′, where R and R′ are the organic parts of the carboxylic acid andalcohol respectively.

The term “dimer” refers to the chemical entity formed by disulfidelinkage of two identical prodrugs, or protected cysteine analogsdescribed herein.

The term “subject” includes humans. The terms “human,” “patient” and“subject” are used interchangeably.

In general, unless indicated otherwise, a chemical group referred toanywhere in the specification can be optionally substituted.

The term “therapeutically effective amount” means the amount of acompound that, when administered to a subject for treating a disease ordisorder, is sufficient to effect such treatment for the disease ordisorder. The “therapeutically effective amount” can vary depending onthe compound, the disease or disorder and its severity, and the age,weight, etc., of the subject to be treated.

In one embodiment, the terms “treating” or “treatment” refer toameliorating the disease or disorder (i.e., arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment, “treating” or “treatment” refers toameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder, or even preventing the same.

In one aspect, the present invention is directed to compounds of formulaI:

whereR¹ is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂,CH₂-phenyl, and phenyl,R⁴ is selected from the group consisting of H, C(O)R₂, and

R² is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂,CH₂-phenyl, and phenyl; andR³ is selected from the group consisting of H, CH₃, CH₂-phenyl,CH(CH₃)₂, CH₂OH,

In another aspect, the present invention is directed to compounds offormula II:

whereR¹ is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂,CH₂-phenyl, and phenyl;R⁴ is selected from the group consisting of H and

R² is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂,CH₂-phenyl, and phenyl; andR³ is selected from the group consisting of H, CH₃, CH₂-phenyl,CH(CH₃)₂, CH₂OH,

Presently preferred compounds include:

Certain compounds described herein may contain one or more chiral atoms,or may otherwise be capable of existing as two enantiomers, or two ormore diastereoisomers. Accordingly, the compounds of this inventioninclude mixtures of enantiomers/diastereoisomers as well as purifiedenantiomers/diastereoisomers or enantiomerically/diastereoisomericallyenriched mixtures. Also included within the scope of the invention arethe individual isomers of the compounds represented by formulas above aswell as any wholly or partially equilibrated mixtures thereof. Thepresent invention also covers the individual isomers of the compoundsrepresented by the formulas above as mixtures with isomers thereof inwhich one or more chiral centers are inverted. Also, it is understoodthat all tautomers and mixtures of tautomers are included within thescope of the compounds of the formulas above.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, e.g hemi-hydrate. In general,the solvated forms, with pharmaceutically acceptable solvents such aswater, ethanol, and the like are equivalent to the unsolvated forms forthe purposes of the invention.

Certain compounds of the invention also form pharmaceutically acceptablesalts, e.g., acid addition salts. For example, the nitrogen atoms mayform salts with acids. Examples of suitable acids for salt formation arehydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, furmaric, succinic, ascorbic, maleic, methanesulfonicand other mineral carboxylic acids well known to those in the art. Thesalts are prepared by contacting the free base form with a sufficientamount of the desired acid to produce a salt in the conventional manner.The free base forms may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous hydroxidepotassium carbonate, ammonia, and sodium bicarbonate. The free baseforms differ from their respective salt forms somewhat in certainphysical properties, such as solubility in polar solvents, but the acidsalts are equivalent to their respective free base forms for purposes ofthe invention. (See, for example S. M. Berge, et al., “PharmaceuticalSalts,” J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein byreference.)

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66:1 et seq. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid. Representative acid addition salts include, but are notlimited to acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptableexcipients.

The phrase “therapeutically effective amount” of the compound of theinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.0001 to about 1000mg/kg/day. If desired, the effective daily dose can be divided intomultiple doses for purposes of administration; consequently, single dosecompositions may contain such amounts or submultiples thereof to make upthe daily dose.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions can be specially formulated for oraladministration in solid or liquid form, for parenteral injection or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, transdermally (e.g. using a patch),transmucosally, sublingually, pulmonary, intraperitoneally, topically(as by powders, ointments or drops), bucally or as an oral or nasalspray. The term “parenterally,” as used herein, refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a component of the present invention and aphysiologically tolerable diluent. The present invention includes one ormore compounds as described above formulated into compositions togetherwith one or more non-toxic physiologically tolerable or acceptablediluents, carriers, adjuvants or vehicles that are collectively referredto herein as diluents, for parenteral injection, for intranasaldelivery, for oral administration in solid or liquid form, for rectal ortopical administration, among others.

Compositions suitable for parenteral injection may comprisephysiologically acceptable, sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), vegetable oils (such asolive oil), injectable organic esters such as ethyl oleate, and suitablemixtures thereof.

These compositions can also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

In another aspect, the invention is directed to a method of treating adisease or condition in a subject comprising administering to thesubject a therapeutically effective amount of a compound of any ofFormulas I or II or a pharmaceutically acceptable salt thereof. Thepreferred route of administering to the subject is via oral delivery.

In particular, the present invention provides methods of treating adisease or condition of the Central Nervous System (CNS), including butnot limited to schizophrenia, drug craving, drug addiction, bipolardisorder, anxiety, depression, Parkinson's disease, Alzheimer's disease,cognitive dysfunction, multiple sclerosis, Amyotrophic lateral sclerosis(ALS), ischemic stroke, HIV dementia, and Huntington's diseasecomprising administering to a subject in need thereof a therapeuticallyeffective amount of any of the inventive compounds.

However, it is within a skill in the art that the provided compounds maybe used to treat other diseases or conditions associated with diminishedglutathione levels and/or glutamate signaling, and/or oxidative stress,and/or impaired cystine-glutamate antiporter activity, glutamateneurotransmission, synaptic connection, and gene expression.

In general, the invention is not limited to treatment of any specificdisease or condition but encompasses the treatment of any disease orcondition whose mechanism may be affected by the compounds of thepresent invention.

In some aspects, the methods and compositions of the invention may beused in combination with conventional first and second generationanti-psychotic agents.

Thus, in one embodiment, the invention is directed to a combinationaluse of: 1) a compound of any of Formulas I-II and 2) pre-existing firstgeneration anti-psychotic agents (including but not limited tochlorpromazine, thioridazine, mesoridazine, loxapine, molindone,perphenazine, thiothixene, trifluoperazine, haloperidol, fluphenazine,droperidol, zuclopenthixol and prochlorperazineperphenazine) and/orsecond generation anti-psychotic agents (including but not limited toamisulpride, aripiprazole, asenapine, blonanserin, clotiapine,clozapine, iloperidone, lurasidone, mosapramine, olanzapine,paliperidone, perospirone, quetiapine, remoxipride, risperidone,sertindole, sulpiride, ziprasidone, zotepine, bifeprunox (DU-127,090),pimavanserin (ACP-103), and vabicaserin (SCA-136)) for the treatment ofa disease or condition of CNS, including but not limited toschizophrenia, drug craving, drug addiction, bipolar disorder, anxiety,depression, Parkinson's disease, Alzheimer's disease, cognitivedysfunction, multiple sclerosis, ALS, ischemic stroke, HIV dementia, andHuntington's disease.

The invention further encompasses pharmaceutical compositions containinga compound of any of Formulas I or II or a pharmaceutically acceptablesalt thereof in combination with a pharmaceutically-acceptable carrier.

Methods of formulating/manufacturing such pharmaceutical compositions(alternatively termed “medicaments”) for the treatment of a disease orcondition in a subject are also within the invention's scope.

For a clearer understanding of the invention, details are providedbelow. These are merely illustrations and are not to be understood aslimiting the scope of the invention in any way. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art from thefollowing examples and foregoing description. Such modifications arealso intended to fall within the scope of the appended claims.

EXAMPLES

Exemplary synthetic strategies are outlined in Schemes 1-3 which yieldS-t-butyl protected cysteine di-peptide analogs according to the presentinvention. No representation has been made that the actual synthesisfollowing Schemes 1-3 has been performed. However, it is believed that aperson of skill in the art would know how to synthesize the claimedcompounds based, in part, on the provided Schemes 1-3.

Schemes 4-10 illustrate the actual synthesis that has been performed tomake some of the compounds of the invention.

wheretBuOH is tert-butanol andR¹ and R² are independently selected from the group consisting of CH₃,CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, and phenyl.

Description of Reactions in Scheme 1

Cysteine (1) is dissolved in a large excess of concentrated (12 N)hydrochloric acid and is treated with a solution of tert-butanol(dissolved in 12 N hydrochloric acid) at room temperature whilestirring. After the addition of tert-butanol, the mixture is heated toreflux for 6 hrs while stirring. When the reaction is completed, themixture is cooled to 0° C. and the precipitating solid, the S-t-butylcysteine (2), is filtered off from the remaining solution.

The S-t-butyl protected cysteine (2) is dissolved in anhydrousconcentrated sulfuric acid and treated with 1.5 molar equivalent of thecorresponding alcohol (R¹OH) drop wise while stirring. After the alcoholaddition, the mixture is allowed to stir under an argon atmosphere for8-12 hrs to ensure reaction completion. The mixture is then added to anice water bath to stop and cool the reaction. The resulting mixture isextracted with methylene chloride (×3) to remove the desired compound(3) from the water layer. The organic level is dried over magnesiumsulfate (or potassium carbonate) and filtered. The resulting organicsolution is condensed under vacuum and solvent is removed from thedesired compound (3). The desired compound (3) is carried over to thenext reaction without additional purification.

The freshly obtained compound (3) is added, to a mixture oftriethylamine and chloroform (1:2) and cooled with an ice bath to 0° C.The resulting mixture is treated with 1.1 molar equivalent of, thecorresponding acyl chloride (R²C(O)Cl) while stirring under an argonatmosphere for 4-6 hrs to produce the desired compound (4). After thereaction is completed, ice water is added to the mixture and the desiredcompound (4) is extracted with methylene chloride (×3) and dried overmagnesium sulfate (potassium carbonate). The final product is obtainedby removing the solvent under vacuum to obtain compound (4).

Synthesis of Compound 4 where R¹ and R² are Methyl

Compound 4 where R¹ and R² are methyl may be prepared, for example, asfollows:

Cysteine (1) is dissolved in a large excess of concentrated (12 N)hydrochloric acid and is treated with a solution of tert-butanol(dissolved in 12 N hydrochloric acid) at room temperature whilestirring. After the addition of tert-butanol, the mixture is heated toreflux for 6 hrs while stirring. When the reaction is completed, themixture is cooled to 0° C. and the precipitating solid, the S-t-butylcysteine (2), is filtered off from the remaining solution.

The S-t-butyl protected cysteine (2) is dissolved in anhydrousconcentrated sulfuric acid and treated with 1.5 molar equivalent ofmethyl alcohol (CH₃OH) drop wise while stirring. After the alcoholaddition, the mixture is allowed to stir under an argon atmosphere for8-12 hrs to ensure reaction completion. The mixture is then added to anice water bath to stop and cool the reaction. The resulting mixture isextracted with methylene chloride (×3) to remove the desired compound(3) from the water layer. The organic level is dried over magnesiumsulfate (or potassium carbonate) and filtered. The resulting organicsolution is condensed under vacuum and solvent is removed from thedesired compound (3). The desired compound (3) is carried over to thenext reaction without additional purification.

The freshly obtained compound (3) is added to a mixture of triethylamineand chloroform (1:2) and cooled with an ice bath to 0° C. The resultingmixture is treated with 1.1 molar equivalent acetyl chloride whilestirring under an argon atmosphere for 4-6 hrs to produce the desiredcompound (4). After the reaction is completed, ice water is added to themixture and the desired compound (4) is extracted with methylenechloride (×3) and dried over magnesium sulfate (potassium carbonate).The final product is obtained by removing the solvent under vacuum toobtain compound (4).

whereR¹ and R² are independently selected from the group consisting of CH₃,CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, and phenyl; andR³ is selected from the group consisting of H, CH₃, CH₂-phenyl,CH(CH₃)₂, CH₂OH,

Description of Reactions in Scheme 2

Cysteine (1) is dissolved in a large excess of concentrated (12 N)hydrochloric acid and is treated with a solution of tert-butanol(dissolved in 12 N hydrochloric acid) at room temperature whilestirring. After the addition of tert-butanol, the mixture is heated toreflux for 6 hrs while stirring. When the reaction is completed, themixture is cooled to 0° C. and the precipitating solid, the S-t-butylcysteine (2), is filtered off from the remaining solution.

The S-t-butyl protected cysteine (2) is dissolved in anhydrousconcentrated sulfuric acid and treated with 1.5 molar equivalent of thecorresponding alcohol (R¹OH) drop wise while stirring. After the alcoholaddition, the mixture is allowed to stir under an argon atmosphere for8-12 hrs to ensure reaction completion. The mixture is then added to anice water bath to stop and cool the reaction. The resulting mixture isextracted with methylene chloride (×3) to remove the desired compound(3) from the water layer. The organic level is dried over magnesiumsulfate (or potassium carbonate) and filtered. The resulting organicsolution is condensed under vacuum and solvent is removed from thedesired compound (3). The desired compound (3) is carried over to thenext reaction without additional purification.

The desired amino acid (5) is added to a mixture of triethylamine andchloroform (1:2) and cooled with an ice bath to 0° C. The resultingmixture is treated with 1.1 molar equivalent of the corresponding acylchloride (R²C(O)Cl) while stirring under an argon atmosphere for 4-6hrs. After the reaction is completed, the mixture is treated with 0.5 NHCl to liberate the carboxylic acid group for future reactions,producing the desired compound (6). The resulting compound (6) isdissolved in stirring methylene chloride and treating with 1.2 molarequivalent of 1,1′-carbonyldiimidazole (CDI) and 1.1 equivalent of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature and allowedto stir for 4 hrs under an argon atmosphere. After the initial reactionis completed, freshly prepared compound (3) (1.2 molar equivalent) isadded slowly to the reaction at room temperature while stirring. Theresulting mixture is allowed to stir for an additional 4 hrs to producethe desired compound (7).

Synthesis of Compound 7 where R¹ and R² are Methyl, R³ is H

To make compound 7 where R¹ and R² are methyl and R³ is hydrogen, thefollowing steps may be taken:

Cysteine (1) is dissolved in a large excess of concentrated (12 N)hydrochloric acid and is treated with a solution of tert-butanol(dissolved in 12 N hydrochloric acid) at room temperature whilestirring. After the addition of tert-butanol, the mixture is heated toreflux for 6 hrs while stirring. When the reaction is completed, themixture is cooled to 0° C. and the precipitating solid, the S-t-butylcysteine (2), is filtered off from the remaining solution.

The S-t-butyl protected cysteine (2) is dissolved in anhydrousconcentrated sulfuric acid and treated with 1.5 molar equivalent ofmethyl alcohol (CH₃OH) drop wise while stirring. After the alcoholaddition, the mixture is allowed to stir under an argon atmosphere for8-12 hrs to ensure reaction completion. The mixture is then added to anice water bath to stop and cool the reaction. The resulting mixture isextracted with methylene chloride (×3) to remove the desired compound(3) from the water layer. The organic level is dried over magnesiumsulfate (or potassium carbonate) and filtered. The resulting organicsolution is condensed under vacuum and solvent is removed from thedesired compound (3). The desired compound (3) is carried over to thenext reaction without additional purification.

The desired amino acid, glycine (5) is added to a mixture oftriethylamine and chloroform (1:2) and cooled with an ice bath to 0° C.The resulting mixture is treated with 1.1 molar equivalent of acetylchloride while stirring under an argon atmosphere for 4-6 hrs. After thereaction is completed, the mixture is treated with 0.5 N HCl to liberatethe carboxylic acid group for future reactions, producing the desiredcompound (6). The resulting compound (6) is dissolved in stirringmethylene chloride and treating with 1.2 molar equivalent of1,1′-carbonyldiimidazole (CDI) and 1.1 equivalent of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature and allowedto stir for 4 hrs under an argon atmosphere. After the initial reactionis completed, freshly prepared compound (3) (1.2 molar equivalent) isadded slowly to the reaction at room temperature while stirring. Theresulting mixture is allowed to stir for an additional 4 hrs to producethe desired compound (7).

whereR¹ and R² are independently selected from the group consisting of CH₃,CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, and phenyl; andR³ is selected from the group consisting of H, CH₃, CH₂-phenyl,CH(CH₃)₂, CH₂OH,

Description of Reactions in Scheme 3

Cysteine (1) is dissolved in a large excess of concentrated (12 N)hydrochloric acid and is treated with a solution of tert-butanol(dissolved in 12 N hydrochloric acid) at room temperature whilestirring. After the addition of tert-butanol, the mixture is heated toreflux for 6 hrs while stirring. When the reaction is completed, themixture is cooled to 0° C. and the precipitating solid, the S-t-butylcysteine (2), is filtered off from the remaining solution.

The desired amino acid (5) is dissolved in anhydrous concentratedsulfuric acid and treated with 1.5 molar equivalent of the correspondingalcohol (R¹OH) drop wise while stirring. After the alcohol addition, themixture is allowed to stir under an argon atmosphere for 8-12 hrs toensure reaction completion. The mixture is then added to an ice waterbath to stop and cool the reaction. The resulting mixture is extractedwith methylene chloride (×3) to remove the desired compound (9) from thewater layer. The organic level is dried over magnesium sulfate (orpotassium carbonate) and filtered. The resulting organic solution iscondensed under vacuum and solvent is removed from the desired compound(9). The desired compound (9) is carried over to the next reactionwithout additional purification.

The S-t-butyl protected cysteine (2) is added to a mixture oftriethylamine and chloroform (1:2) and cooled with an ice bath to 0° C.The resulting mixture is treated with 1.1 molar equivalent of thecorresponding acyl chloride (R²C(O)Cl) while stirring under an argonatmosphere for 4-6 hrs. After the reaction is completed, the mixture istreated with 0.5 N HCl to liberate the carboxylic acid group for futurereactions, producing the desired compound (8). The resulting compound(8) is dissolved in stirring methylene chloride and treating with 1.2molar equivalent of 1,1′-carbonyldiimidazole (CU) and 1.1 equivalent of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature and allowedto stir for 4 hrs under an argon atmosphere. After the initial reactionis completed, freshly prepared compound (9) (1.2 molar equivalent) isadded slowly to the reaction at room temperature while stirring. Theresulting mixture is allowed to stir for an additional 4 hrs to producethe desired compound (10).

Synthesis of Compound 10 where R¹ and R² are Methyl and R³ is H

To synthesize compound 10 where R¹ and R² are methyl and R³ is H, thefollowing steps may be taken:

Cysteine (1) is dissolved in a large excess of concentrated (2 N)hydrochloric acid and is treated with a solution of tert-butanol(dissolved in 12 N hydrochloric acid) at room temperature whilestirring. After the addition of tert-butanol, the mixture is heated toreflux for 6 hrs while stirring. When the reaction is completed, themixture is cooled to 0° C. and the precipitating solid, the S-t-butylcysteine (2), is filtered off from the remaining solution.

The desired amino acid, glycine (5) is dissolved in anhydrousconcentrated sulfuric acid and treated with 1.5 molar equivalent ofmethyl alcohol (CH₃OH) drop wise while stirring. After the alcoholaddition, the mixture is allowed to stir under an argon atmosphere for8-12 hrs to ensure reaction completion. The mixture is then added to anice water bath to stop and cool the reaction. The resulting mixture isextracted with methylene chloride (×3) to remove the desired compound(9) from the water layer. The organic level is dried over magnesiumsulfate (or potassium carbonate) and filtered. The resulting organicsolution is condensed under vacuum and solvent is removed from thedesired compound (9). The desired compound (9) is carried over to thenext reaction without additional purification.

The S-t-butyl protected cysteine (2) is added to a mixture oftriethylamine and chloroform (1:2) and cooled with an ice bath to 0° C.The resulting mixture is treated with 1.1 molar equivalent of acetylchloride while stirring under an argon atmosphere for 4-6 hrs. After thereaction is completed, the mixture is treated with 0.5 N HCl to liberatethe carboxylic acid group for future reactions, producing the desiredcompound (8). The resulting compound (8) is dissolved in stirringmethylene chloride and treating with 1.2 molar equivalent of1,1′-carbonyldiimidazole (CDI) and 1.1 equivalent of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature and allowedto stir for 4 hrs under an argon atmosphere. After the initial reactionis completed, freshly prepared compound (9) (1.2 molar equivalent) isadded slowly to the reaction at room temperature while stirring. Theresulting mixture is allowed to stir for an additional 4 hrs to producethe desired compound (10).

Schemes 4-10 demonstrate the actual synthesis that has been performed toarrive at some of the compounds of the invention. These schemes anddescription of reaction conditions are outlined below.

Description of Reactions in Schemes 4-10

Unless otherwise noted, natural amino acids were used to synthesize thecompounds of the invention.

Preparation of 2-amino-3-tert-butylsulfanyl-propionic acid ethyl esterhydrochloride (12)

To L-cysteine ethyl ester hydrochloride (11) (50.0 g, 0.27 mol) in TFA(320 mL) was added t-BuOH (25.8 mL, 0.27 mol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h, thenconcentrated. To the residue at 0° C. was added water (300 mL), and themixture was basified with NH₄OH (28%) to pH 8, extracted with EtOAc (500mL). The organic phase was washed with sat. NaHCO₃ (100 mL) and brine(100 mL), dried (Na₂SO₄), and concentrated to give a light purple oil(46.0 g), which was dissolved in ether (800 mL) and treated with 4M HClin dioxane (110 mL). The resulting ppt was collected by filtration,washed with ether, and air-dried to provide 12 as a white solid (49.2 g,75%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (br s, 3H), 4.21 (m, 3H), 3.03(m, 2H), 1.29 (s, 9H), 1.24 (t, 3H).

Preparation of 2-amino-3-tert-butylsulfanyl-propionic acid hydrochloride(14)

A solution of L-cysteine (30.3 g, 0.25 mol) and t-BuOH (62.2 mL, 0.65mol) in 2N HCl (110 mL) was heated at 120° C. in a sealed flask for 48h. After cooling, it was concentrated to dryness and triturated withacetone to give 14 as a white solid (45.0 g, 84%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.58 (br s, 3H), 4.06 (t, 1H), 3.03 (m, 2H), 1.29 (s, 9H).

Preparation of 2-amino-3-tert-butylsulfanyl-propionic acid benzyl estertosylate (15)

A mixture of 14 (23.4 g, 109.5 mmol), p-toluenesulfonic acid monohydrate(62.5 g, 328.5 mmol), and benzyl alcohol (56.7 mL, 547.4 mmol) in CHCl₃(320 mL) was refluxed for 4 h by using a Soxhlet apparatus containingdry silica gel. After cooling, CHCl₃ was evaporated and an equal volumeof diethyl ether was added to the residue. The resulting ppt wascollected by filtration, washed with ether, and air-dried to provide 15as a white solid (38.0 g, 79%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (br s,3H), 7.45 (m, 7H), 7.11 (d, 2H), 5.24 (AB, 2H), 4.38 (t, 1H), 3.00 (d,2H), 2.29 (s, 3H), 1.26 (s, 9H).

Preparation of 2-amino-3-tert-butylsulfanyl-propionic acid isopropylester hydrochloride (16)

Thionyl chloride (20 mL) was added to a solution of 14 (20.0 g, 93.6mmol) in i-PrOH (160 mL) at 0° C. slowly. The reaction mixture wasrefluxed for 4 h, then cooled and concentrated. The residue was treatedwith ether (200 mL). The resulting ppt was collected by filtration,washed with ether, and air-dried to provide 16 as a white solid (19.7 g,82%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (br s, 3H), 5.00 (m, 1H), 4.14(t, 1H), 3.03 (m, 2H), 1.29 (s, 9H), 1.26 (d, 3H), 1.24 (d, 3H).

General Procedure A Preparation of propionylamino-acetic acid (A)(09-031-41)

A mixture of 17 (46 mL, 357 mmol) and 18 (10.0 g, 133 mmol) in 19 (164mL) was heated at 150° C. for 10 min. After cooling, water (100 mL) wasadded, and the mixture was concentrated. EtOAc (50 mL) was added, theresulting ppt was collected by filtration, washed with EtOAc (10 mL),and air-dried to provide A as a white solid (12.0 g, 92%) after treatedwith charcoal. ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (br s, 1H), 8.08 (br t,1H), 3.72 (d, 2H), 2.22 (q, 2H), 0.99 (t, 3H).

Preparation of 3-phenyl-2-propionylamino-propionic acid (B)

With General procedure A, starting from 17 (46 mL, 357 mmol) and 20(22.0 g, 133 mmol) in 19 (164 mL), 21.0 g (71%) of B was obtained as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (br s, 1H), 8.08 (d, 1H),7.26 (m, 5H), 4.40 (m, 1H), 3.04 (m, 1H), 2.84 (m, 1H), 2.06 (m, 2H),0.90 (t, 3H).

Preparation of benzoylamino-acetic acid (C)

Compound 18 (10 g, 133 mmol) was dissolved in 10% sodium hydroxidesolution (100 mL), cooled to 15° C., and then benzoyl chloride 21 (21.6mL, 186 mmol) was added in portions to this solution. After theaddition, the mixture was stirred at room temperature for 0.5 h. Crushedice (100 g) was added to the solution and concentrated HCl was addeddropwise until the mixture was acidified (pH 2-3). The resultingcompound C (23 g, 96%) was obtained as a white solid. ¹H NMR (400 MHz,CD₃OD) δ 8.73 (br s, 1H), 7.87 (d, 2H), 7.54 (m, 3H), 4.87 (br s, 1H),4.10 (s, 2H).

General Procedure B Preparation of2-(2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-3-tert-butylsulfanyl-propionicacid ethyl ester (23)

To a mixture of 22 (6.63 g, 25.0 mmol), 12 (6.04 g, 25.0 mmol), HOBt(3.72 g, 27.5 mmol), and DIPEA (4.35 mL, 25.0 mmol) in THF (150 mL) wasadded DCC (5.67 g, 27.5 mmol) in THF (50 mL). The reaction mixture wasstirred at room temperature for 18 h, then EtOAc (200 mL) was added. Themixture was washed successively with 1N HCl (50 mL), sat. NaHCO₃ (50mL), and brine (50 mL), dried (Na₂SO₄), and concentrated. Silica gelchromatography (hexanes/EtOAc 4:1) gave 23 as a colorless sticky mass(8.87 g, 78%). ¹H NMR (400 MHz, CDCl₃) δ 7.26 (m, 5H), 6.60 (br d, 1H),4.99 (br d, 1H), 4.75 (m, 1H), 4.40 (br d, 1H), 4.20 (m, 2H), 3.10 (m,2H), 2.95 (m, 2H), 1.40 (s, 9H), 1.26 (m, 12H).

General Procedure C Preparation of2-(2-amino-3-phenyl-propionylamino)-3-tert-butylsulfanyl-propionic acidethyl ester (D)

To a solution of 23 (6.63 g, 25.0 mmol) in CH₂Cl₂ (30 mL) was added TFA(30 mL) dropwise at 0° C. The reaction mixture was stirred at roomtemperature for 1 h, then concentrated. EtOAc (150 mL) was added, washedsuccessively with sat. NaHCO₃ (2×20 mL) and brine (20 mL), dried(Na₂SO₄), and concentrated to give D as a light yellow oil (6.83 g,99%). ¹H NMR (400 MHz, CDCl₃) δ 7.94 (br d, 1H), 7.30 (m, 5H), 4.80 (m,1H), 4.21 (q, 2H), 3.70 (dd, 1H), 3.28 (dd, 1H), 2.99 (m, 2H), 2.74 (dd,1H), 2.25 (br s, 2H), 1.30 (m, 12H).

Preparation of2-(2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-tert-butylsulfanyl-propionicacid ethyl ester (25)

With General procedure B, starting from 24 (5.43 g, 25.0 mmol) and 12(6.04 g, 25.0 mmol), 7.86 g (78%) of 25 was obtained as a white solid.¹H NMR (400 MHz, CDCl₃) δ 6.59 (br d, 1H), 5.06 (br d, 1H), 4.82 (m,1H), 4.23 (q, 2H), 4.00 (t, 1H), 3.01 (d, 2H), 2.18 (m, 1H), 1.45 (s,9H), 1.30 (m, 12H), 0.98 (d, 3H), 0.93 (d, 3H).

Preparation of2-(2-amino-3-methyl-butyrylamino)-3-tert-butylsulfanyl-propionic acidethyl ester (E)

With General procedure C, starting from 25 (7.86 g, 19.43 mmol), 6.87 g(crude) of E was obtained as a colorless sticky mass. ¹H NMR (400 MHz,CDCl₃) δ 7.76 (br d, 1H), 4.79 (m, 1H), 4.23 (q, 2H), 3.49 (d, 1H), 3.00(d, 2H), 2.27 (m, 1H), 1.30 (m, 12H), 1.02 (d, 3H), 0.95 (d, 3H).

Preparation of2-(2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-3-tert-butylsulfanyl-propionicacid benzyl ester (26)

With General procedure B, starting from 22 (6.63 g, 25.0 mmol) and 15(10.99 g, 25.0 mmol), 11.60 g (90%) of 26 was obtained as a white gum.¹H NMR (400 MHz, CDCl₃) δ 7.38-7.18 (m, 10H), 6.60 (br d, 1H), 5.16 (AB,2H), 5.00 (br s, 1H), 4.80 (m, 1H), 4.40 (br d, 1H), 3.07 (m, 2H), 2.96(d, 2H), 1.40 (s, 9H), 1.22 (s, 9H).

Preparation of2-(2-amino-3-phenyl-propionylamino)-3-tert-butylsulfanyl-propionic acidbenzyl ester (F)

With General procedure C, starting from 26 (5.60 g, 10.88 mmol), 4.50 g(quant.) of F was obtained as a colorless sticky mass. ¹H NMR (400 MHz,CDCl₃) δ 7.26 (m, 10H), 5.15 (s, 2H), 4.75 (m, 1H), 4.00 (m, 1H), 3.09(m, 1H), 2.92 (m, 3H), 1.22 (s, 9H).

Preparation of2-(2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-tert-butylsulfanyl-propionicacid benzyl ester (27)

With General procedure B, starting from 24 (5.43 g, 25.0 mmol) and 15(10.99 g, 25.0 mmol), 10.0 g (86%) of 27 was obtained as a white stickymass. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (m, 5H), 6.59 (br d, 1H), 5.19 (s,2H), 5.05 (br d, 1H), 4.89 (m, 1H), 4.00 (m, 1H), 3.01 (d, 2H), 2.15 (m,1H), 1.44 (s, 9H), 1.27 (s, 9H), 0.95 (d, 3H), 0.90 (d, 3H).

Preparation of2-(2-amino-3-methyl-butyrylamino)-3-tert-butylsulfanyl-propionic acidbenzyl ester (G)

With General procedure C, starting from 27 (10.0 g, 21.4 mmol), 8.50 g(crude) of G was obtained as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.77 (br d, 1H), 7.36 (m, 5H), 5.19 (s, 2H), 4.88 (m, 1H), 3.40 (d, 1H),3.00 (d, 2H), 2.26 (m, 1H), 1.28 (s, 9H), 0.99 (d, 3H), 0.89 (d, 3H).

General Procedure D Preparation of3-tert-butylsulfanyl-2-propionylamino-propionic acid ethyl ester (31)

To a mixture of 12 (11.40 g, 47.15 mmol) and triethylamine (15 mL, 108.0mmol) in dichloromethane (180 mL) was added 28 (4.9 mL, 56.20 mmol) indichloromethane (20 mL) dropwise at 0° C. The mixture was stirred atroom temperature for 18 h, and evaporated. The residue was dissolved inethyl acetate (200 mL), washed with 10% HCl, water, saturated sodiumbicarbonate, brine, dried and evaporated. The residue was purified bycolumn chromatography using EtOAc:Hexane (1:4) as eluent to give thetitle compound (7.39 g, 60%) as a thick oil. ¹H NMR (400 MHz, CDCl₃) δ6.25 (br s, 1H), 4.87 (m, 1H), 4.24 (q, 2H), 3.03 (d, 2H), 2.28 (q, 2H),1.32 (m, 12H), 1.19 (t, 3H). MS m/z 262 (M+1). HPLC: 96.55%(ACQ_PA95C_BLS; Column: BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of 3-tert-butylsulfanyl-2-propionylamino-propionic acidisopropyl ester (32)

With General procedure D, starting from 28 (4.63 g, 50.0 mmol) and 16(10.23 g, 40 mmol), 7.16 g (65%) of the title compound was obtained as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 6.25 (br s, 1H), 5.06 (q, 1H),4.85 (m, 1H), 3.03 (d, 2H), 2.30 (q, 2H), 1.29 (m, 15H), 1.17 (t, 3H).MS m/z 276 (M+1). HPLC: 95.29% (ACQ_PA95_C_BLS; Column:BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of 3-tert-butylsulfanyl-2-propionylamino-propionic acidbenzyl ester (33)

With General procedure D, starting from 28 (4.43 g, 47.88 mmol) and 15(14.61 g, 33.24 mmol), 5.37 g (50%) of the title compound was obtainedas a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (m, 5H), 6.27 (br d,1H), 5.20 (m, 2H), 4.94 (m, 1H), 3.03 (d, 2H), 2.29 (q, 2H), 1.27 (s,9H), 1.17 (t, 3H). MS m/z 324 (M+1). HPLC: 98.52% (ACQ_PA95_C_BLS;Column: BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of 2-benzoylamino-3-tert-butylsulfanyl-propionic acid ethylester (34)

With General procedure D, starting from 21 (5.94 g, 42.26 mmol) and 12(8.54 g, 35.36 mmol), 6.56 g (60%) of the title compound was obtained asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, 2H), 7.52 (m, 3H),6.97 (br d, 1H), 5.06 (m, 1H), 4.28 (q, 2H), 3.16 (m, 2H), 1.32 (m,12H). MS m/z 310 (M+1). HPLC: 98.35% (ACQ_PA95_C_BLS; Column:BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of 2-Benzoylamino-3-tert-butylsulfanyl-propionic acidisopropyl ester (35)

With General procedure D, starting from 21 (5.6 g, 40.4 mmol) and 16(7.33 g, 28.65 mmol), 6.72 g (73%) of the title compound was obtained asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (m, 2H), 7.54-7.43 (m,3H), 6.97 (br d, 1H), 5.12 (m, 1H), 5.02 (m, 1H), 3.14 (dd, 2H), 1.30(m, 15H). MS m/z 324 (M+1). HPLC: 96.61% (ACQ_PA95_C_BLS; Column:BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of 2-Benzoylamino-3-tert-butylsulfanyl-propionic acid benzylester (36)

With General procedure D, starting from 21 (4.2 g, 30.2 mmol) and 15(9.43 g, 21.45 mmol), 5.18 g (65%) of the title compound was obtained asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, 2H), 7.50 (m, 8H),6.98 (br d, 1H), 5.27 (m, 2H), 5.12 (m, 1H), 3.15 (m, 2H), 1.27 (s, 9H).MS m/z 372 (M+1). HPLC: 96.80% (ACQ_PA95_C_BLS; Column:BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

General Procedure E Preparation of3-tert-Butylsulfanyl-2-(2-propionylamino-acetylamino)-propionic acidethyl ester (37)

To a mixture of A (6.55 g, 50 mmol), 12 (12.09 g, 50 mmol), and1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.34 g, 80mmol) in dichloromethane (700 mL) was added 4-(dimethylamino)pyridine(9.15 g, 75 mmol) at room temperature. The mixture was stirred at 40° C.overnight. After cooling down, to the mixture was added dichloromethane(500 mL), washed with 10% HCl (300 mL), saturated sodium bicarbonate(2×300 mL), brine (300 mL), dried over sodium sulfate and evaporated.The residue was purified by column chromatography usingCH₂Cl₂/EtOAc/MeOH (70:28:2) as eluent to afford the title compound (6.20g, 39%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.66 (br d,1H), 6.18 (br s, 1H), 4.81 (m, 1H), 4.23 (m, 2H), 4.00 (dd, 2H), 3.01(d, 2H), 2.28 (q, 2H), 1.30 (m, 12H), 1.87 (t, 3H). MS m/z 319 (M+1).HPLC: 95.65% (ACQ_PA95_C_BLS; Column: BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of2-(2-Benzoylamino-acetylamino)-tert-butylsulfanyl-propionic acid ethylester (38)

With General procedure E, starting from C (4.20 g, 23.4 mmol) and 12(5.66 g, 23.4 mmol), 6.0 g (70%) of the title compound was obtained as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, 2H), 7.53 (m, 3H), 7.18(br s, 1H), 7.07 (br d, 1H), 4.87 (m, 1H), 4.25 (m, 4H), 3.03 (d, 2H),1.30 (m, 12H). MS m/z 367 (M+1). HPLC: 98.57% (ACQ_PA95_C_BLS; Column:BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of3-tert-Butylsulfanyl-2-(3-phenyl-2-propionylamino-propionylamino)-propionicacid ethyl ester (39)

With General procedure E, starting from B (13.26 g, 60.0 mmol) and 12(12.32 g, 51.0 mmol), 4.1 g (16.7%) of the title compound was obtainedas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.31 (m, 5H), 6.46 (br d,1H), 6.07 (br d, 1H), 4.73 (q, 2H), 4.23 (m, 2H), 3.10 (d, 2H), 2.94 (d,2H), 2.23 (q, 2H), 1.31 (m, 12H), 1.13 (t, 3H). MS m/z 409 (M+1). HPLC:95.56% (ACQ_PA95_C_BLS; Column: BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of3-tert-Butylsulfanyl-2-(3-methyl-2-propionylamino-butyrylamino)-propionicacid ethyl ester (40)

With General procedure D, starting from 28 (4.03 g, 43.55 mmol) and E(10.55 g, 34.65 mmol), 7.05 g (57%) of the title compound was obtainedas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 6.54 (br d, 1H), 6.09 (br d,1H), 4.80 (m, 1H), 4.38 (dd, 1H), 4.22 (q, 2H), 3.00 (m, 2H), 2.26 (q,2H), 2.11 (m, 1H), 1.29 (m, 12H), 1.17 (t, 3H), 0.97 (2d, 6H). MS m/z361 (M+1). HPLC: 97.42% (ACQ_PA95_B_BLS; Column: BEH_C18_(—)2-1×50mm_(—)1-7 μm).

Preparation of2-(2-Benzoylamino-3-methyl-butyrylamino)-3-tert-butylsulfanyl-propionicacid ethyl ester (41)

With General procedure D, starting from 21 (4.8 g, 34.15 mmol) and E(9.23 g, 30.32 mmol), 5.60 g (45%) of the title compound was obtained asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (m, 2H), 7.54-7.42 (m,3H), 6.82 (br d, 1H), 6.59 (br d, 1H), 4.83 (m, 1H), 4.59 (dd, 1H), 4.23(q, 2H), 3.01 (m, 2H), 2.24 (m, 1H), 1.30 (t, 3H), 1.27 (s, 9H), 1.06(d, 3H), 1.04 (d, 3H). MS m/z 409 (M+1). HPLC: 98.20% (ACQ_PA95_C_BLS;Column: BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of2-(2-Benzoylamino-3-phenyl-propionylamino)-3-tert-butylsulfanyl-propionicacid ethyl ester (42)

With General procedure D, starting from 21 (6.78 g, 48.23 mmol) and D(15.0 g, 42.55 mmol), 10.12 g (52%) of the title compound was obtainedas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (m, 2H), 7.54-7.30 (m,3H), 7.27 (m, 5H), 6.85 (br d, 1H), 6.56 (br d, 1H), 4.93 (q, 1H), 4.73(m, 1H), 4.21 (m, 2H), 3.22 (m, 2H), 2.94 (d, 2H), 1.29 (t, 3H), 1.23(s, 9H). MS m/z 457 (M+1). HPLC: 98.50% (ACQ_PA95_C_BLS; Column:BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of2-(2-Benzoylamino-acetylamino)-3-tert-butylsulfanyl-propionic acidbenzyl ester (43)

With General procedure E, starting from C (4.48 g, 25.0 mmol) and 15(11.0 g, 25.0 mmol), 3.85 g (36%) of the title compound was obtained aswhite crystals. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (m, 2H), 7.54-7.41 (m,3H), 7.35 (m, 5H), 7.01 (br t, 1H), 6.93 (br d, 1H), 5.19 (s, 2H), 4.90(m, 1H), 4.21 (m, 2H), 3.02 (d, 2H), 1.26 (s, 9H). MS m/z 429 (M+1).HPLC: 95.26% (ACQ_PA95_C_BLS; Column: BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

Preparation of2-(2-Benzoylamino-3-methyl-butyrylamino)-3-tert-butylsulfanyl-propionicacid benzyl ester (44)

With General procedure D, starting from 21 (5.64 g, 40.12 mmol) and G(13.0 g, 35.47 mmol), 5.2 g (31%) of the title compound was obtained asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, 2H), 7.52 (m, 8H),6.83 (br d, 1H), 6.68 (br d, 1H), 5.19 (s, 2H), 4.91 (m, 1H), 4.61 (t,1H), 3.06 (m, 2H), 2.23 (m, 1H), 1.24 (s, 9H), 1.02 (d, 6H). MS m/z 471(M+1). HPLC: 96.20% (ACQ_PA95_C_BLS; Column: BEH_C18_(—)2-1×50 mm_(—)1-7μm).

Preparation of2-(2-Benzoylamino-3-phenyl-propionylamino)-3-tert-butylsulfanyl-propionicacid benzyl ester (45)

With General procedure D, starting from 21 (3.68 g, 26.18 mmol) and F(9.2 g, 22.19 mmol), 5.1 g (44%) of the title compound was obtained as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, 2H), 7.52 (m, 13H), 6.81(br d, 1H), 6.48 (br d, 1H), 5.23 (q, 2H), 4.92 (q, 1H), 4.79 (m, 1H),3.26 (m, 2H), 2.95 (d, 2H), 1.20 (s, 9H). MS m/z 519 (M+1). HPLC: 96.38%(ACQ_PA95_C_BLS; Column: BEH_C18_(—)2-1×50 mm_(—)1-7 μm).

What is claimed is:
 1. A compound of formula I:

where R¹ is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, and phenyl, R⁴ is selected from the group consisting of H; C(O)R₂;

R² is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, and phenyl; and R³ is selected from the group consisting of H, CH₃, CH₂-phenyl, CH(CH₃)₂, CH₂OH,

or a pharmaceutically acceptable salt, ester or prodrug thereof.
 2. A compound of formula II

where R¹ is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, and phenyl; R⁴ is selected from the group consisting of H and

R² is selected from the group consisting of CH₃, CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, and phenyl; and R³ is selected from the group consisting of H, CH₃, CH₂-phenyl, CH(CH₃)₂, CH₂OH,

or a pharmaceutically acceptable salt, ester or prodrug thereof.
 2. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.
 3. A method of treating a disease or condition of the Central Nervous System (CNS) selected from the group consisting of schizophrenia, drug craving, drug addiction, bipolar disorder, anxiety, depression, Parkinson's disease, Alzheimer's disease, cognitive dysfunction, multiple sclerosis, Amyotrophic lateral sclerosis (ALS), ischemic stroke, HIV dementia, and Huntington's disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim
 1. 4. The method of claim 3, wherein said disease or condition of central nervous system is schizophrenia.
 5. The method of claim 3, further comprising administering to a subject in need thereof: a) a first generation anti-psychotic agent selected from the group consisting of chlorpromazine, thioridazine, mesoridazine, loxapine, molindone, perphenazine, thiothixene, trifluoperazine, haloperidol, fluphenazine, droperidol, zuclopenthixol and prochlorperazineperphenazine, and/or b) a second generation anti-psychotic agent selected from the group consisting of amisulpride, aripiprazole, asenapine, blonanserin, clotiapine, clozapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine, bifeprunox (DU-127,090), pimavanserin (ACP-103), and vabicaserin (SCA-136). 